CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer’s disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer’s disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer’s disease and other tau-mediated neurodegenerative diseases

Inflammatory biomarkers in Alzheimer's disease plasma

Introduction:Plasma biomarkers for Alzheimer’s disease (AD) diagnosis/stratification are a“Holy Grail” of AD research and intensively sought; however, there are no well-established plasmamarkers.Methods:A hypothesis-led plasma biomarker search was conducted in the context of internationalmulticenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL;259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed.Results:Ten analytes showed significant intergroup differences. Logistic regression identified five(FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD andCTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI(AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Twoanalytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71).Discussion:Plasma markers of inflammation and complement dysregulation support diagnosis andoutcome prediction in AD and MCI. Further replication is needed before clinical translatio

Migratory behaviour of Baltic salmon (Salmo salar L.) : adaptive significance of annual cycles

This thesis evaluates the adaptive significance of annual cycles on the migratory behaviour of Baltic salmon (Salmo salar L.). The studies have included field experiments as well as laboratory studies gf maturity and migratory behaviour patterns of smolts and postsmolts mainly from the Angerman river population. Contrasting to the phenotypical elasticity in life-history traits, Baltic salmon was found to have a rather strict temporal organization of their annual behavioural patterns. Two year old smolted Baltic salmon showed drastic differences in migratory behaviour when compared in tanks containing either fresh or brackish water. Freshwater kept fish showed an annual cycle where downstream displacement in the upper water column was followed by a stationary behaviour, indicating a readaption to a freshwater life. Fish in brackish water behaved as a migratory fish throughout tne study. Baltic salmon also showed differences in maturation patterns in fresh and brackish water. Three summer old males detained in freshwater all matured sexually the following autumn. If transferred to sea and kept in net- pens a low proportion matured, mainly previously matured males. Furthermore there was a size- dependent relationship of sexual rematuration. Many small previously matured males did not migrate, similarly small previolusly matured males were unable to respond to shifts in the environment. With larger size the alternatives of sexual maturation and high growth rate wi more related to the environmental conditions the fish experienced. A hypothesis has been tested assuming that Baltic salmon migration is influenced by an annual time program. According to the hypothesis the migratory distance covered in the Baltic should be a result of a migratory activity sequence rather than a definite goal orientation. Fish detained before release generally showed a shorter distance between release point and area of recapture compared to fish released at normal time of smoltrun. The migratory distance appeared to be inversly related to the period of delay before release. A seasonal difference in migratory propensity was recorded. An instantaneous mortality curve for Baltic salmon during seaward migration and early sea-phase was estimated based on recapture data on sequentially related fish. The weekly mortality rate decreased from an initial mean of 271 during onset of migration, to 3.51 in mean during autumn. The high risk of mortality during the first part of migration indicated that strong selective forces act on a precise seasonal timing of migration.Diss. (sammanfattning) Umeå : Umeå universitet, 1988, härtill 5 uppsatserdigitalisering@um

Mortality risks of Baltic salmon (Salmo salar L.) during downstream migration and the early sea-phase [Elektronisk resurs] : effects of body-size and season

Mortality risks in Baltic salmon during early migration was estimated through a sequential release experiment. Effects of time of release and size of fish on survival rate were studied. A protected transfer to the sea and an acclimatization prior to release increased the recapture rates by 1.6 to 2.0 times compared to fish released in the river. Furthermore, fish with a delayed release had a 2.8 to 5.0 times higher recapture rate than smolts released in the river. I found a strong positive correlation between the size of the fish and recapture rates during all three experimental years. Mortality rates peaked during the downstream migration and entry in to the sea. The weekly risk of mortality during the two first weeks was estimated to be 27.8%. Thereafter the mortality risk declined rapidly to 6.1% per week during the following 8-9 weeks. From mid September until the end of November the estimated mortality rate was only 3.5% per week. Baltic salmon appears to migrate at a sub-optimal size with respect to survival during migration. A gain in survival by a larger size during migration,could be obtained by a prolonged freshwater residency. However this is considered to be outweighted by the option of an accelerated growth rate in the sea.15 sidor, [1988]digitalisering@um

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